Pharmacogenetics reveal key memory protein complex

Researchers from Baylor College of Medicine have provide the first direct genetic evidence that a complex of proteins known as mammalian target of rapamycin complex 1 (mTORC1) plays a crucial role in memory formation.

The findings, which could have implications in treating those suffering from post traumatic stress disorder and a wide range of cognitive memory disorders, can be found in the current edition of the Proceedings of the National Academy of Sciences.

"In the study we use a drug called rapamycin. We have known that this drug could reduce brain activity that strengthens long-term memory and can partially block long-term memory,"said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and the senior author of the study. "However the effect of the drug could be non-specific. In addition, the evidence that mTORC1 promotes long-term memory and enhances the connection between brain cells has been controversial."

Role in memory formation

Using a multidisciplinary approach, which combines behavior, electrophysiology and molecular biology, the investigators showed that this complex of proteins plays a direct role in memory formation.

The combination approach used by Costa-Mattioli and his research team is called pharmacogenetics. They used a very low dose of rapamycin in combination with a genetic manipulation (mice lacking one copy of the mTOR gene).

"The idea behind this approach is that neither the drug nor the genetic manipulation alone reveals a phenotype. Only the combination of rapamycin and genetic manipulation exhibited a phenotype,"said Dr. Costa-Mattioli. "Given that the lack of mTOR ( both copies), or other regulators, is lethal, this new pharmacogenetic approach allows us to study the role of mTORC1 in brain processes.”

In the experiment, mice were trained to associate a physical stimulation with a particular environment (context). When they were returned to the same environment the next day, only normal mice treated with rapamycin were able to recall the events from the day before. Rapamycin did not affect the strength of the synaptic connection and long-term memory in these mice.

However, in mice lacking one copy of the mTOR gene, rapamycin blocked both long-term changes in synaptic strength and memory formation. These data not only show that rapamycin is specific, but also demonstrate the synergistic interaction of the drug and a genetic manipulation on the same target (mTORC1).

Memory recall

Similar experiments were performed focusing on memory recall. Only the mice lacking one copy of the mTOR gene and treated with rapamycin had lower rates of recall.

"There is a precise moment when we can erase a memory. It occurs right after the moment of recall, when the memory becomes susceptible to disruption,"said Costa-Mattioli. "When signaling pathways are disturbed right after recall, as we did with the pharmacogenetic approach, it results in memory disruption. This finding could lend itself to treating those suffering from post traumatic stress disorder associated with memory of a traumatic event.”

Since the mTORC1 signaling is altered in a variety of cognitive disorders, such as age-related memory loss, Autism Spectrum Disorders or even in Alzheimer’s disease, these findings may also lead to a better way to treat these disorders Costa-Mattioli added.

Others who took part in the research include: Loredana Stoica, Dr. Ping Jun Zhu, Wei Huang, Hongyi Zhou of BCM and Dr. Sara C. Kozma of the University of Cincinnati.

Funding for the research came from George Mitchell and the late Cynthia Mitchell, the Searle Foundation and the Whitehall Foundation.